Ultraviolet B (UVB) irradiation and human papillomavirus (HPV) have been suggested to act as cancer promoting cofactors in epidermis, as epidermal squamous cell carcinomas frequently harbor high risk HPV subtypes and appear in sun-exposed skin. The high risk HPV subtypes are thought to immortalize cells via the action of the E6 and E7 viral oncoproteins, and, as a result, predispose the cells towards cancer progression. These oncoproteins interfere with the function of the p53 and Rb tumor suppressor proteins and alter events at the G1/S interface of the cell cycle. In addition to HPV infection, conversion to malignancy requires subsequent mutation of host cell DNA. It has been suggested that ultraviolet light, a powerful mutagen, may serve to produce these mutations. Unfortunately, cancer-promoting synergy between HPV and UVB has not been definitively demonstrated, in vivo. To study the role of HPV in surface epithelial cancer, we have developed a mouse model of HPV-dependent epidermal disease by expressing the human papillomavirus type 16 E6/E7 oncoproteins in the superficial epidermal layers. These mice display marked epidermal hyperplasia, but not tumor formation-a phenotype that is a hallmark of early HPV-dependent disease. To evaluate the relative contribution of HPV and UVB in skin cancer progression, we will compare the effects of UVB irradiation on disease progression in E6/E7-negative mice. We hypothesize that the presence of the HPV oncoproteins will predispose the mice to UVB- dependent cancer progression. As the HPV oncoproteins and UVB are both known to alter the function of key regulatory proteins in the G1/S transition of the cell cycle, we will focus our effort on studying these regulatory events. We will examine the level, functional activity, and tissue distribution of p53 and Rb (and associated proteins), the cyclins, the cyclin-dependent kinases (cdk), and the cyclin-dependent kinase inhibitors (cdki) during disease progression. The proposed studies are designed to provide new information regarding the role of HPV in each stage of disease progression.